Avid Bioservices Inc (CDMO)

[freethemice]

The other new paper today. More evidence that bavi is being studied as an anti-viral treatment.
Catheterized guinea pigs infected with Ebola Zaire virus allows safer sequential
sampling to determine the pharmacokinetic profile of a phosphatidylserine-targeting
monoclonal antibody
Antiviral Research http://www.sciencedirect.com/science/article/pii/S0166354212002586?v=s5
The coauthors include three Peregrine employees: Kara Corbin-Lickfett, Cyril Empig, Kyle Schlunegger
Abstract
Sequential sampling from animals challenged with highly pathogenic organisms, such as
haemorrhagic fever viruses, is required for many pharmaceutical studies. Using the guinea pig model
of Ebola virus infection, a catheterized system was used which had the benefits of allowing repeated
sampling of the same cohort of animals, and also a reduction in the use of sharps at high biological
containment. Levels of a PS-targeting antibody (Bavituximab) were measured in Ebola-infected
animals and uninfected controls. Data showed that the pharmacokinetics were similar in both
groups, therefore Ebola virus infection did not have an observable effect on the half-life of the
antibody.
[snip]
Bavituximab (PGN401) is a monoclonal human-mouse chimeric antibody, with the variable region
from the mouse IgG3 monoclonal antibody 3G4 that targets phosphatidylserine (PS) joined to the
human IgG1k constant regions (Thorpe, 2010). Whilst PS resides predominantly in the inner leaflet
of the plasma membrane in healthy cells, it externalizes under certain stress conditions, during cell
activation and in cell death via apoptosis (Hengartner, 2000). During this process, PS becomes
available for antibody binding. Initial work with PGN401 focused on its use to target endothelial cells
in tumor vasculature via their PS surface expression (Huang et al., 2005). Bavituximab has completed
Phase II clinical trials in patients with advanced breast cancer and non-small cell lung cancer (Thorpe,
2010), and other Phase II clinical trials are ongoing.
More recently, the effects of PGN401 have been studied in the context of viral infection. Virus induced
events also result in a loss of lipid asymmetry exposing PS on the plasma membrane (Pai et
al., 2009). Binding of PGN401 to these cells results in their elimination through recognition by cells of
the immune system. To date, many of the antiviral properties of PGN401 have been investigated
with hepatitis C virus infections (Sakamoto and Watanabe, 2009), and this work has progressed to
clinical trials (Tomillero and Moral, 2008; Tomillero and Moral, 2009). Studies have also been
undertaken in other viral infections. In 2008, it was reported that PGN401 showed efficacy in guinea
pigs infected with Pichinde virus, a model that closely resembles Lassa fever in humans (Jahrling et
al., 1981), as well as having effects on cells infected with influenza A, vaccinia, vesicular stomatitis
virus and mouse cytomegalovirus (Soares et al., 2008).
Virus induced externalization of PS raises the possibility that PGN401 has broad spectrum antiviral
activity. The advantages of targeting PS include drug specificity for infected cells, and since PS is a
feature of the host cell, effectiveness would potentially not be susceptible to viral escape mutations
(Mir et al., 2009). One such application for a broad spectrum antiviral would be against biodefense
pathogens, such as Ebola virus (EBOV). In addition to important public health problems stemming
from severe disease outbreaks in rural parts of Africa, EBOV also poses a potential bioterrorism
threat and in the past has been included in weapons development programmes (Borio et al., 2002).
Case-fatality rates of the African EBOV species in man are as high as 90%, with no prophylaxis or
treatment available. EBOV has been classified as a Category A biowarfare agent by the Centers for
Disease Control (Bray, 2003) and the development of new strategies against EBOV infection are
required urgently.
[snip]
The half-life of PGN401 was determined to be 30.1 hours in uninfected animals, and 28.4 hours in
the EBOV-infected group, showing similar decays of the monoclonal antibody in serum of guinea pigs
irrespective of EBOV infection status. This will be important for determining optimum dosing
strategies and concentrations of the compound in order to obtain the levels required for effective
antiviral activity. When tested previously in guinea pigs infected with Pichinde virus, PGN401 was
delivered intraperitoneally (Soares et al., 2008). However, this route will be difficult to apply in
humans, so intravenous delivery is preferable and was the principal reason for studying PGN401
pharmacokinetics following this route of administration.
[snip]